The past project periods dissected the biologic heterogeneity of Alzheimer's disease (AD) and found that it is a chronic disease with a preclinical, mild, and dementia phase. We found that co-morbid pathologies contribute to the AD phenotype. We identified many genomic, medical, experiential, and psychological factors associated with cognitive decline and incident AD dementia. Finally, we investigated the neurobiologic pathways linking risk factors to clinical and pathologic AD phenotypes. Interestingly, only genomic variants were associated with cognitive decline and AD dementia, and with AD pathology. Recent GWAS studies have nominated many genomic variants for AD dementia. The overall goal of the proposed continuation is to identify brain proteins and proteoforms linking AD risk genes to AD endophenotypes, i.e., AD pathology and cognitive decline. The proposed study will build on results of recent GWAS by leveraging multi-layered genomic data and post-mortem biospecimens from two ongoing cohort studies of aging and dementia. Aim 1 will sequence and do fine mapping of known AD risk genes to identify sequence variants and haplotypes associated with AD endophenotypes in a Discovery Cohort. Aims two will conduct identical analyses in a Confirmatory Cohort and then conduct pooled analyses of both Cohorts to increase power. Aim three will leverage available DNA methylation, H3K9 histone acetylation, miRNA, RNAseq, and public reference data to identify the molecular pathways linking genomic variants to transcripts and AD endophenotypes. Aim 4 will use liquid chromatography mass spectrometry (LC-MS) proteomics techniques to measure protein and proteoform abundances, and to identify isoforms and post-translational modifications linking AD risk genes to AD endophenotypes. An exploratory aim will assess for pleitropy by exploring the relation of AD risk genes, transcripts, and proteins with other pathologic and clinical phenotypes, and AD risk factors. The proposed study represents the logical next step following the successful AD gene discovery efforts. It uses an innovative and timely approach to integrate genomic, epigenomic, and transcriptomic data from human brain, characterize the molecular events linking AD risk genes to AD endophenotypes. Then it identifies proteins, isoforms, and post-translational modifications linking AD risk genes with AD endophenotypes. These proteins and proteoforms will be high value therapeutic targets. The identification of these proteins will provide new directions for research and treatment and thereby have high and sustained impact in the field.